Acute renal failure has a high morbidity and mortality. We are developing new animal models and studying the mechanisms of disease. We are also screening drugs, and studying mechanisms of action. There is great interest in the renal community for developing new animal models of acute renal failure, since the current models do not represent what happens to patients with sepsis induced ARF, which is about 50% of patients with ARF. We have finished developing a set of new model of sepsis-induced ARF that employ cecal ligation puncture in elderly mice treated with fluids and antibiotics. We get increases in creatinine and modest changes in renal histology - similar to human ARF - along with clear evidence of injury in other organs (lung, liver, muscle, etc). These models are very exciting because the mice are treated with fluids and antibiotics, as occurs to humans with sepsis. We have used the model to screen for drugs that inhibit renal and multiorgan damage. We have found three drugs (Ethyl pyurvate, RDT2, and RDT3) that inhibit renal injury, even when first started 8-12 hours after induction of sepsis. Two of the three drugs inhibit TNF; ethyl pyuruvate also inhibits spesis-induced induction of PAI-1. We have also performed a microarray experiment to search for new drug targets and biomarkers; but the results are not currently available. We have also performed additional studies that investigate the mechanism of disease.